Vitiligo is a pigmentary disorder that leaves patients with disfiguring white skin patches increasing in size over time. Especially for teenagers, the associated change in appearance can be devastating. In recent years, it has become clear that the expansion of lesions is associated with an autoimmune response specifically targeting melanocytes, the pigment-synthesizing cells of the skin. Genes associated with the development of vitiligo support the concept, that vitiligo should be considered a hereditary autoimmune disorder. What remains to be explored is the factors that contribute to the onset of disease, as prevention or intervention should preferably take place at this stage. Patients frequently experience skin trauma prior to the onset of new lesions. Precipitating factors include mechanical injury, contact with bleaching phenols, and overexposure to UV light. Such factors impose stress on the skin, and induce the expression of stress proteins to protect affected cells from undergoing apoptosis. These same stress proteins also serve immunogenic functions, evoking an immune response to the cells from which they are derived. The hypothesis underlying the current project is that stress proteins mediate the initiation of an immune response to melanocytes. Stress proteins aberrantly expressed in actively depigmenting vitiligo skin (including HSP27 and HSP70) will be assessed for their contribution to activation of dendritic cells (DCs), particularly in relation to recently discovered cytotoxic effector functions. Molecules mediating such effectormechanisms will be explored, as will accompanying receptor molecules on targeted melanocytes. Since expression of molecules involved in T cell recognition of melanocytes is altered following stress, the consequences for T cell responses will also be explored. In vitro results will be correlated to gene expression observed in depigmenting vitiligo skin and in skin maintained under stress. Finally, a mouse model will be generated that incorporates knowledge acquired in melanoma research, where vitiligo frequently develops in response to successful tumor immunotherapy. Pelage depigmentation serves as areadout for immune responses directed to melanocytes after immunizing mice with and without stress proteins, to define the role of stress proteins in an in vivo model. The same model will be of use to test the efficacy of therapeutic modalities to be developed for vitiligo in the future.